Dermatology: Practical and Conceptual Commentary | Dermatol Pract Concept. 2024;14(2):e2024154 1 Considerations on The Biologic Gray Zone of Melanocytic Tumors Giorgio Annessi1, Emanuele Annessi1 1 Dermatopathology Unit, Istituto Dermopatico dell’Immacolata, IRCCS, Roma, Italy Citation: Annessi G, Annessi E. Considerations on The Biologic Gray Zone of Melanocytic Tumors. Dermatol Pract Concept. 2024;14(2):e2024154. DOI: https://doi.org/10.5826/dpc.1402a154 Accepted: April 23, 2024; Published: April 2024 Copyright: ©2024 Annessi et al. This is an open-access article distributed under the terms of the Creative Commons Attribution- NonCommercial License (BY-NC-4.0), https://creativecommons.org/licenses/by-nc/4.0/, which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original authors and source are credited. Funding: None. Competing Interests: None. Authorship: All authors have contributed significantly to this publication. Corresponding Author: Giorgio Annessi, MD. Dermatopathology Unit, Istituto Dermopatico dell’Immacolata, IRCCS, Via Monti di Creta 00167, Roma, Italy. E-mail: g.annessi@idi.it Dermatologists are well aware that there exist some melano- cytic lesions which are morphologically very difficult to clas- sify as benign or malignant and consequently of uncertain biological potential. This may be due partly on the biological complexity of such lesions and partly on the limitations of our diagnostic methods. We believe the introduction of new entities in the field of melanocytic lesions should be always accompanied with the formulation of specific, reliable and reproducible clinicopathologic criteria. Furthermore, a new entity makes sense when its recognition is of real practical use for patient management and care. In particular, the aim of the pathologist, despite the complexity of the subject, should be to render diagnoses that are as simple as possible, easy for clinicians to understand and above all that guide an appropriate therapeutic approach. Actually, the World Health Organization (WHO) at- tempt to provide a new classification of melanocytic lesions on the basis of a model of tumor progression seems a bit forced to us (1). In fact, instead of proceeding from histo- logical experience to create a model, WHO started from the theoretical model of tumor progression and within this, they tried to adapt the observations derived from histological experience. This unusual way of proceeding has led to the creation of a series of hypothetical “intermediate” entities, grouped under the term melanocytomas/MELTUMP (BAP-1 inactivated melanocytoma, Deep penetrating melanocytoma, PEM, Atypical Spitz Tumor, STUMP and Atypical cellular blue nevus/melanocytoma) that together would constitute the so-called grey-zone of melanocytic lesions (1-5). In ad- dition, within each of these entities it would be possible to recognize further subtypes on the basis of atypia grading (6). However, although WHO has established apparently specific clinical, histological and genetic criteria for identifying each of these entities, their applicability in daily clinicopatholog- ical practice has proven to be very difficult. In fact, both the clinical and especially the histological criteria are far from being specific and reliable; in particular, interobserver repro- ducibility among pathologists, even the most experienced ones, has turned out to be poor with diagnostic arbitrariness reigning supreme. Overall, this results in a terrible confu- sion of terminology that disorients clinicians and an absolute lack of consensus regarding the treatment of these lesions. To demonstrate this confusion, some authors recommend treat- ing melanocytomas with re-excision followed by periodic ultrasonographic monitoring of the regional nodes and those with major atypical features (MELTUMP) with “…manage- ment as per melanoma of the same thickness”. (7) In prac- tice, they propose the same treatment for melanocytomas/ 2 Commentary | Dermatol Pract Concept. 2024;14(2):e2024154 MELTUMP as for conventional melanomas. This is inex- plicable because the same authors define melanocytomas as lesions that are “...neither nevi nor melanomas...” and that “... it is inaccurate to modulate the management of melano- cytomas on the basis of their histological grade because the relationship between morphological atypia and biological risk has been unproven”. (7) This being the case, what could currently be a different and practical, albeit provisional, solution to the classification of melanocytic lesions of uncertain malignant potential? I like to start from the following undeniable data: all so-called melanocytomas/MELTUMP have the potential to produce lymph node metastases and, albeit rarely, distant metastases (1-5). In particular, the percentage of lymph node metastases appears to be higher than that of conventional melanoma (7). There is no doubt that this biological be- havior more or less overlaps with that we expect from thin melanomas (pT1a and/or pT1b).(8) Consequently, I won- der why melanocytomas/MELTUMP cannot be regarded as peculiar forms of less aggressive melanomas. According to some authors this would not be possible because The Cancer Genomic Atlas only recognizes four genetic types of melano- mas (7). This does not seem to be a good reason, because, in our view, biological behavior is the most important feature that should guide the classification of melanocytic lesions in- stead of genetics. Consequently, we feel that the majority of lesions included in melanocytoma/MELTUMP group should be classified as “Low grade Melanomas (LgM)” precisely in consideration of their potential biological behavior. This terminology is widely used for other types of mesenchimal tumors characterized by intermediate histological features and low metastatic potential. (e.g. low grade fibromyxoid sarcoma, low-grade myofibroblastic sarcoma)(9) and there is no reason why it should not also be extended to melanocytic lesions. Thus, for practical purposes, in addition to the four classic types, we could imagine the existence of a fifth group of melanomas (LgM), including the majority of the so-called melanocytomas/MELTUMP, characterized by a different het- erogeneous genetic profile and a low risk of metastases. The introduction of the term “LgM” could have sev- eral practical advantages. First of all, the term is simple and easily understandable by both clinicians and pathologists. Secondly, it would greatly facilitate histological diagnosis with a consequent increase of interobserver reproducibility. Furthermore, the use of the single term (LgM) would relieve the pathologist of the difficult, at times impossible, task of recognizing a series of confusing, poorly reproducible and purely theoretical histological entities. Again, the term LgM clearly informs clinicians about both the nature of the lesion and the biological behaviour to be expected (low metastatic risk). Finally, It indicates to clinicians the appropriate treat- ment and management of the patient. While waiting for new methods to allow more precise and perhaps personalized diagnoses, at the moment the one proposed seems to me the “less imperfect” solution to the problem of the gray-zone of melanocytic lesions. References 1. Elder DE, Barhnill R, Bastian BC, et al. “Melanocytic tumour classification and the pathway concept” in (2018) WHO Clas- sification of Skin Tumours, 4th Edition, eds. Elder DE, Massi D, Scolyer RA, Willemze R, (lyon, F: IARC), pp 66-75. 2. Barhnill R, Bastian BC, Gerami et al. “Deep penetrating nae- vus and melanocytoma” in (2018) WHO Classification of Skin Tumours, 4th Edition, eds. Elder DE, Massi D, Scolyer RA, Willemze R, (lyon, F: IARC), pp 95-6. 3. Zembowicz A, Calonje E, Mihm MC Jr. “Pigmented epitheliod melanocytoma” in (2018) WHO Classification of Skin Tumours, 4th Edition, eds. Elder DE, Massi D, Scolyer RA, Willemze R, (lyon, F: IARC), pp. 978. 4. Wiesner T, Mihm MC Jr, Scolyer RA. “Combined naevus, in- cluding combined BAP1-inactivated naevus melanocytoma” in (2018) WHO Classification of Skin Tumours, 4th Edition, eds. Elder DE,, Massi D, Scolyer RA, Willemze R, (lyon, F: IARC), pp. 99-101. 5. Barhnill R, Bahrami A, Bastian BC, et al. “Spitz tumours” in (2018) WHO Classification of Skin Tumours, 4th Edition, eds. Elder DE,, Massi D, Scolyer RA, Willemze R, (lyon, F: IARC), pp. 108-10. 6. de la Fouchardiere A, Blokx W, van Kempen LC, Luzar B, et al. ESP, EORTC, and EURACAN Expert Opinion practical recom- mendation for the pathological diagnosis and clinical manage- ment of intermediate melanocytic tumors and rare melanoma variants. Virch Arch 2021;479:3-11. 7. Biologic gray zone of melanocityc tumors in reality: defining “non-conventional” melanocytic tumors. Ferrara G, Gualandi A, Rizzo N. Dermatology Practical and Conceptual 2024 (in press) 8. Keung EZ, Gershenwald JE. The eight edition American Joint Committee on Cancer (AJCC) melanoma staging system impli- cations for melanoma treatment and care. Expert Rev Anticancer Ther 2018;18:775-784. 9. Borderline and malignant fibroblastic/myofibroblastic tumors. In (2014) Enzinger & Weiss’s Soft Tissue Tumors, 6th edn. Goldblum JR, Folpe AL, Weiss SW (Elsevier), pp. 288-340.